Testing suggests TORC1 inhibitors can boost immune system in the elderly

A team of researchers affiliated with Novartis Institutes for Biomedical Research and Biometrics Matters Limited, has found via testing with volunteers that TORC1 inhibitors can boost the immune system in the elderly. In their paper published in the journal Science Translational Medicine, the group describes the study they conducted and the results they found.

Most people know that as we get older our immune systems become less robust—we hear warnings every year of the risk that influenza poses for those over age 65. Because a weaker immune system can lead to possibly preventable deaths, scientists have been looking for ways to either prevent immune system weakening or to bolster it in older people. In this new effort, the researchers suggest they might have found a way to achieve the latter.

Prior research has shown that a protein complex called TORC1 is involved in immune response—it has also been tied to immune system decline in older people. In this new effort, the researchers sought to learn more about it by carrying out a phase 2a clinical trial on the use of two TORC1 inhibitors— RAD001 and BEZ235, in older people. Both drugs are already in common use to treat other ailments, which meant that the team did not have to test them for safety first.

Volunteers in the study included 264 healthy people over the age of 65. Some were given RAD001, others BEZ235, and another group received both. Some were also used as a control group. The volunteers were given doses of their designated drugs for a period of six weeks, and all of them were monitored for a year. Over that time span, every incidence of illness or infection was recorded for all of the volunteers.

The researchers report that those volunteers who had received both drugs had the lowest infection rates—1.49 per person. In contrast, those who received a placebo had an infection rate of 2.41. This, the researchers suggest, indicates that the drugs did boost the immune system. As further proof, they noted that some of the volunteers received flu shots not long after being given the drugs. Testing of those volunteers thereafter showed that they had more influenza antibodies in their bloodstreams indicating the immune system was putting up a healthier fight against the threat of infection.

Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.